**EPA REGISTRATION DIVISION -**  **COMPANY NOTICE OF FILING FOR**

**PESTICIDE PETITION Docket ID Number: EPA**  **- HQ**  **- OPP**  **- 2012**  **- 0357**  **EPA Registration Division contact: Sidney Jackson (703) 305 -**  **7610 Interregional Research Project Number 4**  **Pesticide Petition Number: PP 2E8016**  EPA has received a pesticide petition ( PP 2E8016 ) from Interregional Research Project Number 4 (I R - 4), I R - 4 Project Headquarters, Rutgers, The State University of New Jersey , 500 College Road East, Suite 201W, Princeton, NJ 08540 , prop osing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of h ex ythiazox (4 - chloropheny l) - 4 - methyl - 2 - oxo - 3 - thiazolidi ne moiety ) in or on the raw agricultural commodit ies P epper / E ggplant subgroup 8 - 10B at 1.5 parts per million (ppm ), F ruit, pome, group 11 - 10 at 0.25 ppm, Caneberry subgroup 13 - 07A at 1.0 ppm, Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13 - 07F at 1.0 ppm, and Berry , low growing, subgroup 13 - 07G at 3.0 ppm . Further, this petition proposes to delete existing tolerances established in 40 CFR 180.448 for hexy thiazox for Pome Fruit Crop Group 11, Caneberry

Subgroup 13A, grape, and strawberry once the proposed tolerance s have been established since the proposed new tolerances will supersede the existing tolerances . EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of the FDDCA; however, EPA has not f ully evaluated the sufficiency

of the submitted data at this time or whether the data support granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. The nature of the r esidues in plants is adequatel y understood for purposes of this tolerance. Metabolism studies in fruit crops, radish and tea have been previously

reviewed by

the Agency . The Agency has determined th at the residues of concern are h ex ythiazox and its metab olites containing the (4 - chlorophen yl ) - 4 - methyl - 2 - oxo - 3 - thiazolidine moiety. 2. Analytical method. A practical anal yt ical method, high pressure liquid chromatograph y with a ultra violet ( UV ) detector, which detects and measures residues of hex ythiazox and its metabolites as a common moiety , is available for enforcement purposes with a limit of detection that allows monitoring of food with residues at or above the levels set in this tolerance. 3. Magnitude of residues. Seven field trials and three greenhouse trials on bellpepper and an additional three field trials on nonbell peppers were conducted under the

IR - 4 P roject in support of the proposed label amendment (national use) for P epper/ Eg gplant subgroup 8 - 10B. The results of these trials support the proposed tolerance level of 1.5 ppm in/on pepper/eggplant subgroup 8 - 10B . B. Toxicological Profile 1. Acute toxicity. A battery of acute toxicity studies places technical grade h ex ythiazox in Toxicity

Category I V for acute oral L D50 (LD50 > 5,000 milligram/kilograms (mg/kg)), Category III for dermal LD50 (LD50 >5,000 mg/kg), Category III for inhalation L C50 (LC50 >2.0 mg/L), Category III for primary

ey e irritation (showed mild irr itation as reddened conjunctiva), Category I V for dermal irritation (non irritant). Hex ythiazox is a non - sensitizer. Acute toxicological studies place technical grade h ex ythiazox in Toxicology Category I II. 2. Genotoxicty. The following genotoxicity studies were all negative: Ames gene mutation, CHO gene mutation, CHO chromosome aberration, mouse micronucleus and rat hepatocy

te unscheduled DNA s ynthesis. 3. Reproductive and developmental toxicity. Ina developmental toxici ty study in rats, the maternal No - Observed - Adverse - Effect - Level (NOAEL) was 240 mg/kg/day and the maternal Lowest - Observed - Adverse - Effect - Level (LOAEL) was 720 mg/kg/day based on increased ovarian weights and decreased bone ossification. In a developmental toxicity study in rabbits, the maternal NOAEL was 1,080 mg/kg/day (HDT); the maternal LOAEL was not determined. The developmental NOAEL was 1,080 mg/kg/day (HDT); the developmental LOAELwas not determined. In a 2 - generation reproduction study in rats, the parental NOAEL was 35 mg/kg/day and the parental LOAEL was 200 mg/kg/day

based on decreased body weight gain, decreased food consumption and efficiency , and increased liver, kidney and ovarian weights. The reproductive NOAEL was 35 mg/kg/day

and the rep roductive LOAEL was 200 mg/kg/day based on decreased pup b ody weight during lactation, delay ed hair growth and ey e opening. 4. Subchronic toxicity. Ina 1 - month feeding stud y in dogs, the NOAEL was 1.75 mg/kg/day

and the LOAELwas 12.5 mg/kg/day , based o n increased liver and adrenal weights. 5. Chronic toxicity. Ina 1 - ye ar feeding stud y in dogs, the NOAEL was 2.5 mg/kg/day

and the LOAELwas 12.5 mg/kg/day , based on increased alkaline phosphatase, increased adrenal and liver weights, and liver and adrenal lesions. In a carcinogenicity

study in mice, the NOAEL was 36 mg/kg/day and the LOAELwas 215 mg/kg/day . Effects were decreased bod y weight in males and increased hepatocellular carcinomas and combined adenoma/carcinomas. In a chronic feeding/ carcinogenicit y stud y in rats, the NOAEL (s ys temic) was 26 mg/kg/day

and the LOAEL(s ys temic) was 180 mg/kg/day based on decreased body weight gain and increased liver weights in both sexes.A 2009 report from the Cancer Assessment Review Committee (CARC) (September

02, 2009, PC Code 128849, TXR 0055255) noted that the NOAEL of 2.5 mg/kg/day , from the one ye ar toxicity study in dogs, used in establishing the chronic reference dose (RfD) is approximately

65 - fold lower than the lowest dose (163 mg/kg/day) that induced tumors. Thus, the chronic RfD of 0.025 mg/kg/day would be protective of all chronic effects including potential carcinogenicity of hexythiazox. The CARC concluded that the evidence as a whole was not strong enough to warrant the use of a lin ear low dose extrapolation model applied to the animal data (Q1*) for a quantitative estimation of human risk, as had been previously as sessed in October 16, 1998, [63 FR55540]. 6. Animal metabolism. The metabolism of hex ythiazox has been studied in goats , hens and rats. Metabolic pathway s in the animal are similar to those in plants. 7. Metabolite toxicology . There are no metabolites of toxicological concern based on a differential metabolism between plants and animals. 8. Endocrine disruption . No specific test s have been conducted with hexy thiazox to determine whether the chemical may have an y effect in humans that is similar to an effect produced b y a naturally oc c urring estrogen or other endocrine effects. However, there were no significant find ings in other relevant toxicity tests, i.e., teratology

and multi - generational reproduction studies, which would suggest that hex ythiazox produces effects characteristic of the disruptions of hormones. C. Aggregate Exposure 1. Dietary exposure. Dietary Exposure from food. A dietary risk assessment for all registered crops (at the time of the assessment) has been completed b y the Agency (March 17, 2010, 75FR12691.) i. Food. Acute Exposure . No acute endpoint has been identified in the toxicological stud ies for hex ythiazox; therefore, a quantitative acute dietary exposure assessment is unnecessary . Chronic Exposure . A tier 1 chronic risk assessment indicates that the proposed use results in a dietary risk of not more than 65 .4 % of the chronic Population Adjusted Dose (cPAD) for an y population. ii. Drinking W

ater . The Agency

used screening level water exposure models in the dietary

exposure analy sis and risk assessment for hexy thiazox in drinking water. Based on the Pesticide Root Zone Model/Exposure Ana ly sis Modeling S ys tem (PRZM/EXAMS) the estimated drinking water concentration (EDWC) of hexy thiazox for chronic exposures for non - cancer and cancer assessments is estimated to be 4.1 parts per billion (ppb) for surface water. Since surface water residue va lues greatly exceed groundwater EDWCs, surface water residues were used in the dietary risk assessment (July 14, 2010 75FR40741). 2. Non - dietary exposure . HED has conducted a residential risk assessment to support approved uses on turf, ornamental landscape plantings, ornamental plants, orchids and residential fruit trees, nut trees and caneberries. The Agency concludes that there are no residential risks of concern associated with these uses (January 28, 2010EPA Memo. PR Code: 128849, DP Barcode D372889.)

D. Cumulative Effects EPA has not found that hex ythiazox shares a common mechanism of toxicity with an y other substance. E. Safety Determination 1 . U.S. population. Acute risk . No adverse effect resulting from a single oral exposure to hex ythiazox has been identified, thus hexy thiazox is not expected to pose an acute risk. Short - and intermediate term risk . EPA has concluded the combined short - term food, water, and residential exposures result in aggregate MOEs of 16,000 for adults and 2,000 for children. Because EPA's level of concern for hex ythiazox is a MOE of 100 or below, these MOEs are not of concern. Chronic risk . Chronic exposure to hex ythia zox from food and water will utilize no more than 6 5 .4 % of the cPAD for (children 1 - 2 y ears old) the population group receiving the greatest exposure. This assessment utilized existing tolerance values, assumed 100% crop treated, and utilized default pro cessing factors. Chronic residential exposure to residues of hex ythiazox is not expected. 2. Infants and children . Based on these risk assessments, it can be concluded that there is a reasonable certainty that no harm will result to the general population, or to infants and children from aggregate exposure to hexy thiazox residues. F. International Tolerances No national or transnational maximum residue levels (MRL s) for hex ythiazox exist apart from those in the United States.